Effect of the trifluoroacetyl group on the direction of the recyclization of the pyrazine ring in 6-trifluoroacetylpyrrolo[1,2-a]pyrazinium salts

Article abstract of DOI:10.1007/s10593-007-0225-4

A cyclotransformation of 6-trifluoroacetylpyrrolo[1,2-a]pyrazinium salts involving the trifluoroacetyl group carbon atom was discovered and investigated.

Full text of DOI:10.1007/s10593-007-0225-4

Chemistry of Heterocyclic Compounds, Vol. 43, No. 11, 2007
EFFECT OF THE TRIFLUOROACETYL
GROUP ON THE DIRECTION OF THE
RECYCLIZATION OF THE PYRAZINE
RING IN 6-TRIFLUOROACETYL-
PYRROLO[1,2-a]PYRAZINIUM SALTS
V. I. Terenin and A. S. Ivanov
A cyclotransformation of 6-trifluoroacetylpyrrolo[1,2-a]pyrazinium salts involving the trifluoroacetyl
group carbon atom was discovered and investigated.
Keywords: pyrrolo[1,2-a]pyrazine, pyrrolo[1,2-a]pyrazin-1-one, cyclotransformation.
The enamine rearrangement of the pyrazine ring has been demonstrated early for the bicyclic aromatic
pyrrolo[1,2-a]pyrazine system [1]. It was established that 1-alkyl and 1-aralkyl derivatives recyclize by the
action of ethanolic solutions of alkylamines to give 8-alkylaminoindolizines. The introduction of
electron-withdrawing substituents into the starting aza ring is known to enhance the electrophilicity of this ring
and, as a result, facilitate its opening by the action of a nucleophile [2].
In the present work, we show that 6-trifluoroacetylpyrrolo[1,2-a]pyrazinium salts 1a-c containing a
methylene group at C(1) are converted by the action of ethanolic methylamine into 3-trifluoro-
acetyl-8-methylaminoindolizines at lower temperature (70°C) than the 1-alkyl or 1-aralkyl analogs, which
undergo a similar transformation at 140°C. 6-Acylpyrrolo[1,2-a]pyrazin-1-ones 3a,b,d-g are formed in addition
to the expected products of the Kost-Sagitullin rearrangement 2a-c.
7
8
2
1
8a
6
8a
2
3
6
R
NHMe
R1
8
O
1
F3C
F3C
R
MeNH2
N
N
N
+
+
N
O
O
4
O
N
5
Me
7
Me
3
–
I
1a–g
3a,b,d–g
2a–c
1, 3 a R = Et, b R = n-Pr, d R = i-Pr, e R = cyclo-C5H9, f R = Ph, g R = 2-thienyl;
1 c R = PhCH2; 2 a R1 = Me, b R1 = Et, c R1 = Ph
Salts 1a,b containing a methylene group at C(1) participate in two parallel cyclotransformations leading
to a mixture of 8-methylaminoindolizines 2a,b and pyrrolo[1,2-a]pyrazin-1-ones 3a,b.
__________________________________________________________________________________________
M. V. Lomonosov Moscow State University, 119899 Moscow, Russia; e-mail: vter@org.chem.msu.ru.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1714-1719, November, 2007. Original
article submitted June 9, 2006.
1460
0009-3122/07/4311-1460©2007 Springer Science+Business Media, Inc.

Change in the reaction conditions significantly affects the ratio of the recyclization products.
Indolizines 2a,b predominate in the reaction mixtures at 140°C, while 1,2-dihydropyrrolo-
[1,2-a]pyrazin-1-ones 3a,b predominate at 30°C. This discrepancy is evidently a function of the ratio of the rates
of the two independent reactions, leading to products of fundamentally different cyclotransformations.
The opening of the pyrazine ring occurs by the action of aqueous solutions of a wide variety of
nucleophiles such as NH2NH2, NH2OH, (CH2NH2)2, and EtNH2 and is terminated, following the thin-layer
chromatography results, in formation of 2-methyl-1,2-dihydropyrrolo[1,2-a]pyrazin-1-ones, which indicates an
intramolecular mechanism of transformation of the aza ring.
If aqueous methylamine is used as the reagent in the reaction with salts 1a,b,d-g, only products of
recyclization involving the carbonyl carbon atom of the trifluoroacetyl group are formed.
The rearrangement of salts 1d-g without a methylene group at C(1) leads only to pyrrolo-
[1,2-a]pyrazin-1-ones 3d-g by the action of both aqueous and ethanolic methylamine.
The formation of the products of recyclization involving the methylene group was not observed in the
reaction of N-methyl-1-isopropyl-6-trifluoroacetylpyrrolo[1,2-a]pyrazinium
iodide (1d) or N-methyl-
1-cyclopentylpyrrolo[1,2-a]pyrazinium iodide (1c) with methylamine [3]. This failure is probably the result of
higher rate of cyclization to the trifluoroacetyl group in comparison with the possible competing reaction.
The reaction of N-methyl-1-benzyl-6-trifluoroacetylpyrrolo[1,2-a]pyrazinium iodide (1c) with ethanolic
methylamine gives only 8-methylamino-7-phenyl-6-trifluoroacetylindolizine (2c) since the rate of formation of
2c is higher than the rate of the competing cyclization involving the carbonyl carbon atom of the trifluoroacetyl
group.
Salt 1c reacts due to the enhanced CH-acidity of the methylene group with aqueous methylamine to give
a stable base anhydride 4, which does not undergo recyclization under conditions for the enamine rearrangement
of the pyrrolo[1,2-a]pyrazinium salts even upon heating at 140°C for 20 h.
F3C
CHPh
Me
MeNH2
H2O
F3C
Ph
N
N
+
–
N
O
I
N
O
Me
4
1c
Stupnikova et al. [4] have described the formation of a base anhydride from N-methyl-
1,2-dimethylbenzo[b]thieno[2,3-c]pyridinium iodide by the action of methanolic methylamine, which does not
undergo the Kost-Sagitullin rearrangement upon heating at 100°C for 10 h.
The mechanism of the reaction studied entails initial attack of the nucleophile at C(1) or C(3) of the
pyrrolo[1,2-a]pyrazine system. The preference of the nucleophilic attack is not obvious but an unstable
σ-adduct 5 was isolated in the reaction of aqueous methylamine with N-methyl-1-isopropyl-6-trifluoroacetyl-
pyrrolo[1,2-a]pyrazinium iodide (1d) at room temperature.
NHMe
Me
F3C
N
Me
Me
N
O
5
1
The H NMR spectrum of σ-adduct 5 shows signals for the pyrazine protons at higher field than for the
signals of these protons in 1-isopropyl-6-trifluoroacetylpyrrolo[1,2-a]pyrazine, while the coupling constants are
enhanced, indicating nonaromatic character of the aza ring. The upfield part of the spectrum shows signals for
two diastereotopic methyl substituents belonging to the isopropyl group located next to an asymmetric site.
1461

The opening of the pyrazine ring upon attack of the nucleophile both at C(1) and C(3) in the pyrazine ring
leads to acyclic intermediates A and B, which participate in two parallel cyclotransformations. Intramolecular
cyclization of intermediate B results in intermediate C and the subsequent restoration of aromaticity in C leads to
indolizine 2.
F3C
R1
N
+
N
O
Me
–
I
NMe
R1
F3C
NHMe
R1
F3C
N
N
O
O
MeHN
A
NMe
B
HO
F3C
NMe
R1
NMe
R1
F3C
N
N
N
O
Me
D
C
NHMe
–MeNH2
–CHF3
–MeNH2
+H2O
R1
O
NHMe
F3C
N
N
N
O
O
R1
Me
2
3
The second pathway involves attack of the enamine nitrogen in intermediate A at the carbonyl carbon
atom of the trifluoroacetyl group to give intermediate D, which undergoes an unusual step with the loss of
trifluoromethane to give pyrazinone 3.
This scheme is in accord with the effect of the reaction medium on the rearrangement pathway. In
aqueous solutions, the imine component in intermediate A is hydrolyzed to give the corresponding ketone. In
this case, the formation of B or its enol analog is either impossible (when CH2R = Ph or 2-thienyl) or proceeds
much more slowly than the attack of the enamine component on the trifluoroacetyl group, leading to
pyrazinone 3.
A nucleophilic recyclization proceeding as the exchange of exocyclic carbon fragments by cyclic
fragments has been observed for the ethyl ester of nicotinic acid [5] and involves the exchange of C(1) by C(2).
O
O
C(2)
OEt
C(1)–H
C(1)–H
C(2)
O
+
N
N
Me
Me
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The cyclotransformation of pyrrolo[1,2-a]pyrazinium salts 1a,b,d-g to give 6-acyl-2-methylpyrrolo-
[1,2-a]pyrazin-1-ones 3a,b,d-g proceeds as the exchange of two atoms C(1)–C(2) in the ring by exocyclic atoms
C(3)–C(4).
O
C(2)
C(3)
C(3)
C(1)
R
C(2)
R
C(4)
O
F3C
O
N
C(1)
N
C(4)
+
N
N
Me
Me
Thus, this rearrangement belongs to a previously unknown structural type and is a new means to obtain
6-acylpyrrolo[1,2-a]pyrazin-1-ones.
EXPERIMENTAL
1
The H NMR spectra were taken on a Varian VXR-400 and Bruker Avance 400 spectrometers at 400
MHz in CDCl3 at 28°C with TMS as the internal standard. The mass spectra were taken on a Kratos MS-90
spectrometer with 70 eV ionizing radiation. The IR spectra were taken on a UR-20 spectrometer for a film in
CCl4. The course of the reactions and purity of the products were monitored by thin-layer chromatography on
Silufol plates with benzene and 1:1 benzene–ethyl acetate as the eluents.
Preparation of 2-Methyl-6-trifluoroacetylpyrrolo[1,2-a]pyrazinium Iodides (General Method). A
mixture of corresponding 1-alkyl-, 1-aryl-, or 1-aralkyl-6-trifluoroacetylpyrrolo[1,2-a]pyrazine (3 mmol) and
methyl iodide (5 ml) was heated for 5-7 h in a sealed ampule at 70°C until a precipitate formed. The precipitate
was filtered off and washed several times with hot heptane.
Preparation of Indolizines 2a-c and Pyrazinones 3a,b,d-g (General Method). A. A mixture of
quaternary salt 1a-g (1 mmol) and 40% methylamine in absolute ethanol (5 ml) was heated in a sealed glass
ampule for 3-5 h. The reaction mixture was evaporated. The residue was separated by chromatography on a
column of silica gel 35/70 in benzene with increasing polarity of the eluent to 1:2 benzene–ethyl acetate.
Preparation of Pyrazinones 3a,b,d-g (General Method). B. A mixture of quaternary salt 1a-g
(1 mmol) and 40% aqueous methylamine (5 ml) was heated in a sealed glass ampule on a water bath for several
minutes until the salt was completely dissolved. The reaction mixture was left for 24 h at room temperature until
formation of a precipitate. The precipitate was filtered off, recrystallized from acetone, and dried on a glass filter.
In the case of salt 1c, base anhydride 4 was formed as dark-red precipitate, which was filtered off and
recrystallized from heptane.
7-Methyl-8-methylamino-6-trifluoroacetylindolizine (2a). Mp 118-120°C (hexane). 1H NMR
spectrum, δ, ppm (J, Hz): 2.31 (3H, s, CH3); 3.15 (3H, s, NHCH3); 6.72 (1H, d, J = 5.5, H-1); 6.83 (1H, d,
J = 6.9, H-6); 7.56 (2H, dq, J = 5.5, J = 2.1, H-2); 9.45 (1H, d, J = 6.9, H-5). Mass spectrum, m/z (Irel, %): 256
[M]+ (100), 187 [M-CF3]+ (57), 159 [M-COCF3]+ (46). Found, %: C 56.35; H 4.21; N 10.85. C12H11F3N2O.
Calculated, %: C 56.25; H 4.29; N 10.93.
7-Ethyl-8-methylamino-6-trifluoroacetylindolizine (2b). Mp 112-114°C (hexane). 1H NMR spectrum,
δ, ppm (J, Hz): 1.27 (3H, t, J = 7.6, CH2CH3); 2.66 (2H, q, J = 7.6, CH2CH3); 3.12 (3H, s, NHCH3); 6.73 (1H,
dd, J = 5.6, J = 0.5, H-1); 6.87 (1H, d, J = 6.9, H-6); 7.56 (1H, dq, J = 5.6, J = 2.3, H-2); 9.50 (1H, d, J = 6.9,
H-5). Mass spectrum, m/z (Irel, %): 270 [M]+ (100); 201 [M-CF3]+ (44); 158 [M-COCF3]+ (98). Found, %:
C 57.41; H 4.81; N 10.21. C13H13F3N2O. Calculated, %: C 57.77; H 4.81; N 10.37.
1
8-Methylamino-7-phenyl-6-trifluoroacetylindolizine (2e). Mp 68-70°C (pentane). H NMR spectrum,
δ, ppm (J, Hz): 2.99 (3H, s, NHCH3); 4.1 (1H, br. s, NH); 6.84 (1H, d, J = 5.2, H-1); 6.83 (1H, d, J = 6.9, H-6);
1463

7.44-7.59 (5H, m, C6H5); 7.62 (1H, dq, J = 5.2, J = 2.3, H-2); 9.50 (1H, d, J = 6.9, H-5). 13C NMR spectrum, δ,
ppm (J, Hz): 34.9 (NHCH3); 104.6 (C(1)); 117.9 (C(3)); 118.0 (q, J = 289, CF3); 118.6 and 121.2 (C(5) and C(6));
124.5 (q, JC-F = 3.8, C(2)); 124.9 (C(8a)); 128.2 (p-C6H5); 128.8 and 129.2 (m-, o-C6H5); 135.4 (ipso-C6H5); 137.3
(C(7)); 137.8 (C(8)); 160.6 (q, JC-F = 36.0, C=O). Mass spectrum, m/z (Irel, %): 318 [M]+ (100); 249 [M-CF3]+ (41);
159 ([M-COCF3]+ (33). Found, %: C 64.52; H 3.83; N 8.81. C17H13F3N2O. Calculated, %: C 64.15; H 4.08;
N 8.80.
2-Methyl-6-propionylpyrrolo[1,2-a]pyrazinone (3a). Mp 223-225°C (acetone). IR spectrum, ν, cm-1:
1640, 1660, 1680 (C=O, C=C). 1H NMR spectrum, δ, ppm (J, Hz): 1.25 (3H, t, J = 7.3, C(O)CH2CH3); 2.94 (2H,
q, C(O)CH2CH3); 3.51 (3H, s, NCH3); 6.55 (1H, d, J = 6.0, H-3); 7.11 (1H, d, J = 4.3, H-8); 7.26 (1H, d, J = 4.3,
H-7); 8.55 (1H, d, J = 6.0, H-4). Mass spectrum, m/z (Irel, %): 204 [M]+ (64); 175 (100); 151 (57); 120 (80).
Found: C 63.78; H 5.20; N 12.67%. C11H12N2O2. Calculated, %: C 63.70; H 5.92; N 12.63.
6-Butyryl-2-methylpyrrolo[1,2-a]pyrazinone (3b). Mp 198-200°C (acetone). IR spectrum, ν, cm-1:
1640, 1680 (C=O, C=C). 1H NMR spectrum, δ, ppm (J, Hz): 1.03 (3H, t, J = 7.6, C(O)CH2CH2CH3); 1.77 (each
2H, m, C(O)CH2CH2CH3); 2.86 (2H, t, J = 7.6, C(6)(O)CH2CH2CH3); 3.51 (3H, s, NCH3); 6.54 (1H, d, J = 5.9,
H-3); 7.10 (1H, d, J = 4.1, H-8); 7.24 (1H, d, J = 4.1, H-7); 8.57 (1H, d, J = 5.9, H-4). Mass spectrum, m/z
(Irel, %): 218 [M]+ (77); 190 (37); 175 (100); 147 (40). Found, %: C 66.04; H 6.74; N 12.84. C12H14N2O2.
Calculated, %: C 66.04; H 6.47; N 12.83.
6-Isobutyryl-2-methylpyrrolo[1,2-a]pyrazinone (3d). Mp 150-153°C (acetone). IR spectrum, ν, cm-1:
1640, 1670 (C=O, C=C). 1H NMR spectrum, δ, ppm (J, Hz): 1.23 (6H, d, J = 6.9, C(O)CH(CH3)2); 3.38 (1H, m,
C(O)CH(CH3)2); 3.55 (3H, s, NCH3); 6.53 (1H, d, J = 6.4, H-3); 7.23 (1H, d, J = 4.0, H-8); 7.24 (1H, d, J = 4.0,
H-7); 8.58 (1H, d, J = 6.4, H-4). Mass spectrum, m/z (Irel, %): 218 [M]+ (100); 175 (92); 147 (35). Found, %:
C 66.25; H 6.41; N 13.09. C12H14N2O2. Calculated, %: C 66.04; H 6.47; N 12.83.
6-Cyclopentylcarbonyl-2-methylpyrrolo[1,2-a]pyrazinone (3e). Mp 93-94°C (acetone). IR spectrum,
1
ν, cm-1: 1630, 1670 (C=O, C=C). H NMR spectrum, δ, ppm (J, Hz): 1.10-1.25 (8H, m, C(O)CH(CH2)4); 3.41
(1H, m, C(O)CH(CH2)4); 3.53 (3H, s, NCH3); 6.52 (1H, d, J = 6.2, H-3); 7.22 (1H, d, J = 4.0, H-8); 7.23 (1H, d,
J = 4.0, H-7); 8.56 (1H, d, J = 6.2, H-4). Mass spectrum, m/z (Irel, %): 244 [M]+ (29); 175 (100); 147 (22); 124
(38). Found, %: C 63.40; H 6.60; N 10.95. C14H16H2O2. Calculated, %: C 63.83; H 6.60; N 11.46.
6-Benzoyl-2-methylpyrrolo[1,2-a]pyrazinone (3f). Mp 211-212°C (acetone). IR spectrum, ν, cm-1:
1630, 1680 (C=O, C=C). 1H NMR spectrum, δ, ppm (J, Hz): 3.55 (3H, s, NCH3); 6.60 (2H, d, J = 6.1, H-3); 7.09
(1H, d, J = 3.9, H-8); 7.13 (1H, d, J = 3.9, H-7); 7.50 (2H, t, J = 7.4, H (m-C6H5)); 7.60 (1H, tt, J = 7.4, J = 1.2,
H (p-C6H5)); 7.82 (2H, m, H (o-C6H5). Mass spectrum, m/z (Irel, %): 252 [M]+ (100); 175 (57); 105 (50). Found,
%: C 71.21; H 4.74; N 10.90. C15H12N2O2. Calculated, %: C 71.42; H 4.79; N 11.11.
TABLE 1. Yields of Recyclization Products
Yield, %
Starting salt
Product
(sec., MeNH2 ethanol) at Т, °C
(sec, MeNH2 aq.) at Т, °C
30
70
140
30
70
1а
2а
3а
10
39
49
11
45
6
—
35
—
49
1b
2b
3b
15
50
40
25
44
10
28
—
40
43
78
55
56
—
52
55
81
60
1c
1d
1e
1f
2c
3d
3e
3f
60
45
50
47
44
69
43
47
36
39
70
40
45
27
25
1g
3g
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2-Methyl-6-thenoylpyrrolo[1,2-a]pyrazinone (3g). Mp 205-206°C (acetone). IR spectrum, ν, cm-1:
1630, 1680 (C=O, C=C). 1H NMR spectrum, δ, ppm (J, Hz): 3.54 (3H, s, NCH3); 6.58 (1H, d, J = 6.0, H-3); 7.17
(1H, d, J = 4.2, H-8); 7.17 (1H, d, J = 4.2, H-7); 7.20 (1H, dd, J = 4.0, J = 2.7, H (β'-Th)); 7.39 (1H, d, J = 4.2,
H-7); 7.71 (1H, d, J = 4.0, H (α-Th)); 7.84 (1H, d, J = 2.7, H (β-Th)); 8.42 (1H, d, J = 6.0, H-4). Mass spectrum,
m/z (Irel, %): 260 [M+2]+ (6), 258 [M]+ (100), 175 (43), 120 (44), 111 (85). Found, %: C 60.38; H 3.86; N 9.25.
C13H10N2O2S. Calculated, %: C 60.46; H 3.87; N 9.30.
1-Benzylidene-6-trifluoroacetyl-1,2-dihydropyrrolo[1,2-a]pyrazine (4) was obtained in 71% yield
when the reaction was carried out at 30°C, mp 145-146°C (hexane). IR spectrum, ν, cm-1: 1650 (C=O). 1H NMR
spectrum, δ, ppm (J, Hz): 3.18 (3H, s, NCH3); 5.50 (1H, s, C(1)=CH); 5.71 (1H, d, J = 4.7, H-8); 6.20 (1H, d,
J = 6.0, H-3); 7.00 (1H, dq, J = 4.7, JH-F = 2.2, H-7); 7.20-7.40 (5H, m, H (C6H5)); 7.70 (1H, d, J = 6.0, H-4).
Mass spectrum, m/z (Irel, %): 318 [M]+ (36), 205 (15), 91 (100). Found, %: C 64.12; H 4.01; N 8.75.
C17J13F3N2O. Calculated, %: C 64.15; H 4.08; N 8.80.
1-Isopropyl-2-methyl-1-methylamino-1,2-dihydrotrifluoroacetylpyrrolo[1,2-a]pyrazine (5) was
1
obtained in 67% yield, H NMR spectrum, δ, ppm (J, Hz): 0.87 and 0.98 (each 3H, both d, J = 6.9, CH(CH3)2);
2.15 (1H, m, CH(CH3)2); 2.20 (3H, s, NHCH3); 2.83 (3H, s, NCH3); 6.04 (1H, d, J = 6.0, H-3); 6.17 (1H, d,
J = 4.4, H-8); 7.12 (1H, d, J = 6.0, H-4); 7.16 (1H, m, H-7).
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